Process for the manufacture of ketones of the cyclopentano polyhydrophenanthrene series



Patented July 20, 1943 PROCESS "THELMANUFACTURE OF KE- TONES: OF THE CYCLOPENTANO POLY- 'HYDROPHENAN THRENE SERIES a Willy Logemann, Berlin-Friedman, and Walter Hildebrand, Berlin-Pankow,

Germany, as-,

signors to Schering Corporation,;Bloomfield,

N. J.. a corporation of New Jersey t 7 No Drawing; Application December22, 1939, se-

" f rial No. 310,540. Germany January 6, 1939 t 10 Claims.

, This invention relates to an improvement in manufacturing ketones of the cyclopentano polyhydrophenanthrene series and is a further def velopment of the process of the, copending appli cation Serial No. 2l3,630, oiSerini and Logemann filed June 14,1938." 1 t I: s

In such application there is described the splitting off of water from cyclopentano polyhydrophenanthrene, compounds having a hy- "drox yl' g'roup'and the group .--CH.OI-ICH2.0H a inl'l-position and thus obtaining a compound With cortin-like activity (see also Berichte der deutschen Chemischen Gesells chaft, vol. 171, "(1938); page 1364), This processis carriedout with comparatively unfavourableiyield on employing agents which are usually employed for splittingofi water. l

Now, the present invention represents animprovement inthe method of splitting ofifacid .froin glycerol and glycol derivativesfasdescribed in the above-mentioned. application and consists in treatingsaid startingmaterials'withzinc in finelyidivided form. V L t I As' starting materials there may beused'not only cyclopentano polyhydrophenanthrene ccmpoundshaving a'hydr'oxy group at acarbon atom offtheringsystem but also such compounds wherein this hydroxy, group is replaced by a "group convertible ther'einto as, for instancatan ester ether group and the likefand at ,the same carbon atom ,a side-chain of the gneraliornjiula -.CHRCH2R1 1 s wherein R indicates a hydroxy group or a group convertible thereintosior instance,by hydrolysis, such as an, ester group and the like and R1 represents hydrogen or a hydroxy group or a groupconvertible thereinto. In these compounds other substituents may be present in the ring system, such as hydroxyl or keto groups or groups, convertible thereinto, especially at'the carbonatom 3. Suitable starting materials are mentioned more in detail in the copending application Ser. No. 213,630. s

By the process according to this invention ketonic compounds having a sidechain oi the general formula v m s l .COCH2.R1 s ""yv her'ein R1 has the above-described meaning'are obtained by splitting off the hydroxy group from thecarbon atom bearing said side-chain. j

a t e tmen l ij n divided at- T group. t 25- pecially with zinc dust is preferably carried out at elevated temperature and under reduced pressure;

be obtained according to methods known per se, for instance, according to the above mentioned copending application and Berichte der deutschen" Chemischen Gesellschaftff 'vol. -71, '(1938), pages 1313 fifand pages 1362 if, t

Especially valuable compounds are prepared on employing as starting-material compounds having the above described side-chain at the car bon atom 17. Thus, for instance, desoxycorticosterone acetate can be, obtained from pregnantrial-17.20. 21-one-3 diacetate and pregnenolon acetate from pregnentriol-3.17.20-diacetate-3.20

with good yieldsaid pregnenolon acetate being .readily convertible into the corpus luteumhor- "mone, pregnendione-3.20, by oxidation accord:-

ing to methodsiknown. perse. v

The process may be illustrated by the followingformulae wherein It represents a group convertible into a hydroxy group, especially an ester CHgR CH: OH, HR

water but the acid forming the acid radical of said ester group, is split off.

The following examples illustrate the invention without, however, limiting the same to them. a

Example 1 acetate-20.21 are intimately Qmixedvvith 1.1'Igs.

The compounds I used as starting ,inaterials can i tated by the addition of ether.

to a temperature of 150-1'70 C. at a pressure of mm. 51 mgs. sublime at this tempera-, ture. After recrystallisation of the sublimate from acetone-pentane the compounds melt at l52-155'C. -It is identical with desoxycorti-. costerone'acetate with respect to optical rotation value and melting point. The yield of pure substance is 45%.

Example 2 In the same manner 0.1 g.- of pregnene trioldiacetate are mixed with 1.1 gs. of zinc dust and then sublimed.

Pregnenolone acetate is obtained having a1. melting point of I'm-171 C. It yields after sa-' ponification and oxidation with aluminum iso-'- propylate in the presence of cyclohexanone preferably followed by a treatment with acid,.preg

nendione.

Example 3 A mixture of 0.1 g. of 'allo-pregnanetetrol triacetate are sublimed with 1.1 gs. of zinc dust in a high vacuum according to the previous examples. Thereby allo-pregnandiolon diacetate is obtained.

Example 5 200' Rigs.- of As-e-pregnentriol-3.17.20-diace- --tat'e'-3.20 are intimately mixed with 2 gs. of zinc dust in an agate mortar and heated to 120 C. at a pressure of about 0.01 mm. Hg. Colourless needles sublime into the neck of the retort and are removed therefrom by chloroform whereby a small amount of a difficultly solubleby-product remains. The chloroform solutions. of several charges and theresidue remaining after evaporation of the chloroform are dissolved in very little acetone. From the acetone solution a byproduct which is insoluble in ether is precipi- It is filtered off andlthe filtrate is distilled to dryness. The residue yields after redissolving from aqueous acetone, leaflets having a melting point of 158166 C. By'recrystallisation from alcohol pure 17 -isopregnenol-3-one-20-acetate is obtained having a melting point of 169-171 C. Yield: 110 mgs. from 200 mgs. of diacetate. .L g

In order to split off acetic acid, the isomeric A5-e-pregnentriol-3.17.20-diacetate-320 or the mixture of isomers produced, for instance, according to Example 4 of application Serial No. 276,076 can be used. In any case the same reaction product is obtained.

350 mgs. of 1'7-iso-pregnenolon-acetate are dissolved in 20 ccs. of methanol and boiled for minutes after addition of 200 mgs. of potassium bicarbonate dissolved in 4 cos. of water. The reaction solution is then poured into water whereupon the precipitated saponification product is filtered off. 235 mgs. of leaflets crystallize from aqueous alcohol having a melting point of 160165 C. which rises up to 170l72 C. after repeated recrystallisation from dilute alcohol.

Of course, many. changes and variations may be made in the starting materials used, the temperatures employed, the duration of reaction,

in the art in accordance with the principles set cyclopentano,

forth herein and in the claims annexed hereto.

What we claim is:

1. Process for the production of ketones of the cyclopentano polyhydrophenanthrene series, comprising heating and reacting compounds of the cyclopentano polyhydrophenanthrene series having at the 17-.carbon atom of the ring system a, member of the class consisting of the hydroxy group and. groups convertible thereinto with the .=aid of hydrolysis, and also a side-chain of the formula' CHRCH2.R1 wherein'R' is a member of the class consisting of a hydroxy group and a group convertible thereinto and R1 consists of a member of the class composed of hydrogen, a hydroxy group and groups convertible thereinto with the aid of hydrolysis. with zinc particles.

2. Process according to claim 1, wherein zinc dust in a finely divided state is employed.

3. Process for the productionof ketones of the cyclopentano polyhydrophenanthrene series, comprising heating and reacting compoundsof the cyclopentano polyhydrophenanthrene series having at the 17-carbon atom of the ring system an ester group and also a side-chain of the formula -CHR--CH2.R1 I wherein R is a member of the class consisting of a hydroxyl group and a group convertible thereinto with the aid. of hydrolysis, and, R1 is a member of the class consisting of hydrogen, a. hydroxy group and groups convertible thereinto with the aid of hydrolysis, with zinc dust.

4. Process according to claim 1, whereinRiand R1 each consists of an estergroup.

5. Process for the manufacture of ketones of the cyclopentano polyhydrophenanthrene series, comprising heating and reacting a pregnentriol- 3.17.20, wherein not more than .two hydroxy groups are esterified, with zinc dust.

'6. Process for the manufacture of ketones of the cyclopentano polyhydrophenanthrene series, comprising heating and. reacting apregnentriol- 3.17.20, wherein one of the 17- and ZO-hydroxy groups is esterified, with zinc dust.

"7. Process for the manufacture of 'ketones of the cyclo entano polyhydrophenanthrene series, comprising, heating and reacting pregnentriol- 17.20.21-one-3, wherein the hydroxy groups are esterified, with zinc dust.

, 8. Process; for the manufacture of ketones of the cyclopentano polyhydrophenanthrene series comprising heating and reacting pregnentrioh 17.20.21-one-3, wherein the hydroxy groups are partially 'esterified, with zinc dust.

"9. Process for the productionof ket'ones ofv the polyhydrophenanthrene series, comprising heating and reacting compounds of the cyclopentano polyhydrophenanthrene series having at the l'l carbon atom of. the ring system a member of the class consisting of the hydroxy group and groups convertible thereinto with the aid of hydrolysis, and also'a side-chainof the formula -CHRCH2.R1 wherein R is a member of theclass consisting of a hydroxy group and a group convertible thereinto and R1 consists of a member of the class composed of hydrogen, a hydroxy group and groups convertible thereinto with the aid of hydrolysis, with zinc dust. 10. Process for the production ofketonesof the cyclopentano polyhyd p l r d 1 comprising heating and reacting compounds of the cyclopentano polyhydrophenanthrene series having at the 17-carbon atomof the ring system v wherein R is a. member of the class consisting of a hydroxy group and a group convertible thereinto and R1 consists of a memberof the class composed of hydrogen, a. hydroxy group and groups convertible thereinto with the aid of y- 5 drolysis, with zinc dust, in a vacuum.

WILLY LOGEMIANN. WALTER HILDE-BRAND. 

